Our laboratory has been actively studying the molecular mechanisms of alcoholic liver disease, focusing on (1) the role of interleukin-6 (IL-6) and IL-10 and their downstream signal STAT3 in alcoholic fatty liver and liver inflammation;(2) the role of natural killer (NK) cells in alcoholic liver fibrosis. IL-6/IL-10/STAT3 in alcoholic liver disease We have previously demonstrated that IL-6 plays an important role in protecting against liver injury in several murine models of alcoholic liver injury, nonalcoholic fatty liver disease, fatty liver transplantation, and T cell hepatitis. It is believed that the action of IL-6 is mediated via activation of signal transducer and activator of transcription 3 (STAT3). Immunohistochemistry analyses show that phosphorylated STAT3 (STAT3 activation) are detected in hepatocytes, sinusoidal endothelial cells, bile duct-like cells, and inflammatory cells (macrophages, neutrophils etc) in human alcoholic cirrhotic livers. By using liver-specific and macrophage/neutrophil-specific STAT3 knockout mice, we have demonstrated that hepatocyte STAT3 inhibits alcoholic fatty liver but promotes liver inflammation, while myeloid STAT3 inhibits alcoholic liver inflammation. Interestingly, IL-6-deficient mice are more susceptible to alcohol-induced fatty liver and liver injury (hepatocyte apoptosis), while hepatocyte-specific STAT3 knock out mice are only more susceptible to alcohol-induced hepatic steatosis and have similar hepatocyte apoptosis after alcohol feeding compared to wild type mice. This suggests that the hepatoprotection of IL-6 in alcoholic liver injury may be mediated via activation of STAT3-independent signals in hepatocytes, activation of STAT3 in nonparenchymal cells, or both. Our recent studies suggest that endothelial cell STAT3 plays an important role in preventing alcohol-induced liver injury and inflammation. Compared to wild type mice, endothelial cell specific STAT3 knock out mice are more susceptible to alcohol-induced liver inflammation, hepatocyte and endothelial cell apoptosis. Currently, we are also exploring the role of IL-10 in alcoholic liver disease. Abrogation of the anti-fibrotic effect of NK/IFN-gamma contributes to ethanol acceleration of liver fibrosis Chronic alcohol drinking accelerates liver fibrosis in patients with viral hepatitis that cannot be fully explained by ethanol-enhanced liver damage. Recently, we identified a novel mechanism by which alcohol accelerates liver fibrosis: inhibition of the antifibrotic effects of natural killer (NK) cells and interferon-gamma (IFN-gamma). CCl(4) treatment induced greater fibrosis and less apoptosis of HSCs in ethanol-fed mice compared with pair-fed mice. Polyinosinic-polycytidylic acid (Poly I:C) or IFN-gamma treatment inhibited liver fibrosis in pair-fed but not in ethanol-fed mice. Poly I:C activation of NK cell cytotoxicity against HSCs was attenuated in ethanol-fed mice compared with pair-fed mice, which was due to reduced natural killer group 2 member D (NKG2D), tumor necrosis factor-related apoptosis-inducing ligand, and IFN-gamma expression on NK cells from ethanol-fed mice. In vitro, HSCs from ethanol-fed mice were resistant to IFN-gamma-induced cell cycle arrest and apoptosis compared with pair-fed mice. Such resistance was due to diminished IFN-gamma activation of signal transducer and activator of transcription 1 (STAT1) in HSCs from ethanol-fed mice caused by the induction of suppressors of cytokine signaling proteins and the production of oxidative stress. Finally, HSCs from ethanol-fed mice were resistant to NK cell killing, which can be reversed by transforming growth factor-beta1 (TGF-beta1) neutralizing antibody. In conclusion: chronic ethanol consumption attenuates the antifibrotic effects of NK/IFN-gamma/STAT1 in the liver, representing new and different therapeutic targets with which to treat alcoholic liver fibrosis. In addition, we are also collaborating with Drs. George Kunos and Pal Pacher from NIAAA to investigate the role of the endocannabinoid system in alcoholic liver disease.